DESCRIPTION: Regenerative proliferation has been shown to occur in the mature auditory sensory epithelium of the inner ear in some animal models following sound damage and antibiotic toxicity. In these models epithelial repair involves the stimulation of proliferation of cells in the supporting population; some of these supporting cell progeny then differentiate into new receptor hair cells which replace those lost as a consequence of the damage. This cellular recovery process also leads to functional recovery of hearing. These observations in animal model systems have suggested that an effective approach to the treatment of those hearing disorders which result from the loss of hair cells might be to stimulate the production of replacements. The long-term objective of the proposed studies is to elucidate the molecular signals and signaling pathways which control proliferation and differentiation in the cochlear sensory epithelium. This objective will be pursued using the chick basilar papilla model system, in which preliminary studies described in this application have provided evidence for the involvement of the cAMP-dependent signaling pathway in regenerative proliferation. The specific aims are directed to: 1) Determining whether the involvement of the pathway I proliferation in the sensory epithelium is a general phenomenon, rather than specific to a given mode of damage. 2) Identifying the key components of this pathway utilized by the basilar papilla, and the manner in which cross-talk between signaling pathways may be involved. 3) Determining the physiological manner by which the regenerative proliferation pathway(s) is activated in the damaged sensory epithelium. These aims will be pursued using a combination of pharmacological, analytical biochemical, and molecular biological approaches. These approaches involve the application to the basilar papilla in short-term explant culture of agents which inhibit or stimulate specific components of the cAMP and other signaling pathways, the biochemical activity assays of key participants in the pathways under various discriminatory conditions, and the determination of changes in gene expression resulting from pathway interventions. Results obtained from the proposed studies will help define the molecular events which signal and control regenerative proliferation in the cochlear sensory epithelium. Such data are required for the design of therapeutic approaches aimed at the stimulation of new receptor hair cell production for the potential treatment of hearing loss.